Publications by authors named "Andreas Merkenschlager"

68 Publications

Unusual mechanical failures of intrathecal baclofen pump systems: symptoms, signs, and trouble shooting.

Childs Nerv Syst 2021 Apr 8. Epub 2021 Apr 8.

Division of Neuropediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, Leipzig, Germany.

Introduction: Although intrathecal baclofen (ITB) therapy is an effective treatment for spasticity, it has several disadvantages and a risk of complications.

Methods: We present six pediatric patients who suffered from unusual mechanical failures of intrathecal baclofen pump systems.

Results: With these case-vignettes, we provide a systematic approach on how to interpret the symptoms of ITB complications and an advice which further diagnostic and therapeutic steps to follow. We underline the seriousness of baclofen overdose, underdosing or withdrawal.
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http://dx.doi.org/10.1007/s00381-021-05154-3DOI Listing
April 2021

Germline AGO2 mutations impair RNA interference and human neurological development.

Nat Commun 2020 11 16;11(1):5797. Epub 2020 Nov 16.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
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http://dx.doi.org/10.1038/s41467-020-19572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670403PMC
November 2020

Hemiplegic Migraine in Glut1 Deficiency Syndrome and Paroxysmal Dyskinesia at Ketogenic Diet Induction: Case Report and Literature Review.

Mov Disord Clin Pract 2020 Nov 6;7(8):965-970. Epub 2020 Oct 6.

Division of Neuropaediatrics, Hospital for Children and Adolescents University Hospital Leipzig Leipzig Germany.

Background: A rare symptom of Glut1 deficiency syndrome (Glut1 DS) is hemiplegic migraine (HM).

Case: We report a patient with Glut1 DS with a mild phenotype. His leading symptom was HM. As an unusual complication of the initiation of a ketogenic diet (KD), our patient developed paroxysmal nonkinesigenic dyskinesia. Paroxysmal dyskinesia occurred first and exclusively at the initiation of KD.

Literature Review: There are a few case reports for HM in Glut1 DS. All patients had additional neurological symptoms. Regarding central nervous system symptoms such as paroxysmal dyskinesia triggered by KD, we found only 1 other case report.

Discussion: HM is part of the symptom complex of Glut1 DS and can be effectively treated by KD. Paroxysmal dyskinesia trigged by the initiation of KD should not lead to the discontinuation of the diet in Glut1 DS.
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http://dx.doi.org/10.1002/mdc3.13087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604676PMC
November 2020

The Phenotypic Spectrum of PRRT2-Associated Paroxysmal Neurologic Disorders in Childhood.

Biomedicines 2020 Oct 28;8(11). Epub 2020 Oct 28.

Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, 45711 Datteln, Germany.

Pathogenic variants in , encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in . The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic variants and expands the associated phenotypic spectrum.
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http://dx.doi.org/10.3390/biomedicines8110456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719266PMC
October 2020

Quantitative T1 mapping of the normal brain from early infancy to adulthood.

Pediatr Radiol 2021 Mar 17;51(3):450-456. Epub 2020 Oct 17.

Department of Pediatric Radiology, University of Leipzig, Liebigstraße 20a, 04103, Leipzig, Germany.

Background: Quantitative mapping of MRI relaxation times is expected to uncover pathological processes in the brain more subtly than standard MRI techniques with weighted contrasts. So far, however, most mapping techniques suffer from a long measuring time, low spatial resolution or even sensitivity to magnetic field inhomogeneity.

Objective: To obtain T1 relaxation times of the normal brain from early infancy to adulthood using a novel technique for fast and accurate T1 mapping at high spatial resolution.

Materials And Methods: We performed whole-brain T1 mapping within less than 3 min in 100 patients between 2 months and 18 years of age with normal brain at a field strength of 3 T. We analyzed T1 relaxation times in several gray-matter nuclei and white matter. Subsequently, we derived regression equations for mean value and confidence interval.

Results: T1 relaxation times of the pediatric brain rapidly decrease in all regions within the first 3 years of age, followed by a significantly weaker decrease until adulthood. These characteristics are more pronounced in white matter than in deep gray matter.

Conclusion: Regardless of age, quantitative T1 mapping of the pediatric brain is feasible in clinical practice. Normal age-dependent values should contribute to improved discrimination of subtle intracerebral alterations.
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http://dx.doi.org/10.1007/s00247-020-04842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897197PMC
March 2021

Cerebrospinal fluid findings in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies. Part 2: Results from 108 lumbar punctures in 80 pediatric patients.

J Neuroinflammation 2020 Sep 3;17(1):262. Epub 2020 Sep 3.

Department of Neurology, Medical Faculty, Heinrich Heine University Dusseldorf, Düsseldorf, Germany.

Background: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD).

Objective: To describe systematically the CSF profile in children with MOG-EM.

Material And Methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively.

Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age.

Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.
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http://dx.doi.org/10.1186/s12974-020-01825-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470445PMC
September 2020

Association of sleep characteristics with adiposity markers in children.

J Pediatr Endocrinol Metab 2020 Jul;33(7):845-852

IFB Adiposity Diseases, Leipzig University, Leipzig, Germany.

Background Accumulating evidence suggests a relationship between sleep alterations and overweight/obesity in children. Our aim was to investigate the association of sleep measures other than obstructive sleep apnea or sleep duration with overweight/obesity and metabolic function in children. Methods We conducted a prospective cohort study in school- aged children (aged 5 to 8 years, prepubertal, and 12 to 15 years, pubertal) with overweight/obesity and normal-weight children. All children underwent a standardized in-laboratory polysomnography followed by a fasting blood assessment for glucose and metabolic testing. Subjective sleep measures were investigated by a 7-day sleep diary and questionnaire. We analyzed prepubertal and pubertal groups separately using logistic regression and partial correlation analyses. Results A total of 151 participants were analyzed. Overweight/obese children had significantly higher odds for arousal index (prepubertal children: 1.28, Confidence interval (CI): 1.06, 1.67; pubertal children: 1.65, CI: 1.19, 2.29) than normal-weight children, independent of age and gender. In prepubertal children, arousal-index was positively associated with C-peptide (r=0.30, p=0.01), whereas Minimum O2 saturation was negatively associated with triglycerides (r=-0.34, p=0.005), adjusting for age and sex. However, associations were attenuated by further adjustment for body mass index standard deviation scores (BMI-SDS). In pubertal children, higher level of apnea-hypopnea-index and pCO2 predicted increased lipoprotein (a) levels (r=0.35, p=0.03 and r=0.40, p=0.01, respectively), independent of age, sex, and BMI-SDS. A negative association was found between pCO2 and high-density lipoprotein (HDL)-cholesterol (r=-0.40, p=0.01). Conclusions Overall, we report that sleep quality as measured by arousal index may be compromised by overweight and obesity in children and warrants attention in future intervention programs.
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http://dx.doi.org/10.1515/jpem-2019-0517DOI Listing
July 2020

High association of MOG-IgG antibodies in children with bilateral optic neuritis.

Eur J Paediatr Neurol 2020 Jul 15;27:86-93. Epub 2020 Apr 15.

Department of Pediatric Neurology, Children's Hospital Datteln, University Witten/Herdecke, Germany. Electronic address:

Background: Bilateral optic neuritis (bilON) is a rare clinical presentation often thought to be associated with relapsing disorders such as neuromyelitis optica spectrum disorders (NMOSD) or multiple sclerosis (MS).

Objective: To characterize the clinical, radiological phenotype and antibody status of children presenting with bilON.

Material And Methods: Retrospective multicenter study on children with bilON age <18 years with a first episode aquired demyelinating syndrome (ADS), cMRI, AQP4- and serum MOG-antibody status and follow-up data were collected.

Results: 30 patients (f:m = 15:15, median age 8.0y) with bilON met the inclusion criteria. 22/30 (73%) were MOG-positive (median: 1:1280, range: 1:160-1:1520). No patient showed AQP4-abs. 4/30 patients (13%), all with high MOG-abs titers, had recurrent episodes. No patient developed MS. Improvement after IVMP was observed in most patients (26/30; 87%). Outcome was favorable with no sequelae in 22/30 patients. Serial MOG-abs titers tested in 15/22 patients decreased to a median of 1:160 (range: 0-1:640) over a period of 31 months (range: 2-141 months) in 14/15 (93%) patients. MR imaging showed a predominantly anterior affection of the visual system in seropositive patients with bilateral intraorbital lesions in 68% (15/22), compared to 25% in MOG-negative patients (2/8).

Conclusion: Pediatric bilON is associated with high MOG-abs titers in combination with anterior involvement of the visual system. Despite severe loss of vision, the majority of patients shows distinct recovery after IVMP.
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http://dx.doi.org/10.1016/j.ejpn.2020.04.002DOI Listing
July 2020

The "Ivy-Sign" in Moyamoya Disease-From MRI Pattern to Diagnosis.

Neuropediatrics 2020 08 31;51(4):241-244. Epub 2020 Mar 31.

Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany.

Moyamoya disease (MMD) is characterized by bilateral, chronic progressive stenosis at the terminal portions of the internal carotid arteries and their proximal branches. The "smoke-like" appearance of the arterial collaterals in angiography gives the disease its name. The "ivy-sign" is the less-known magnetic resonance imaging (MRI) pattern of this disease. The leptomeningeal collaterals present as diffuse signal enhancement at the brain surface in contrast-enhanced T1-weighted image and fluid-attenuated inversion recovery sequences "as if overgrown with ivy."We report on three patients with MMD in whom the "ivy-sign" was already present but misinterpreted in the initial MRI of the brain. The correct diagnosis was made only after repeated MRI.Using three case studies, we describe the difficulties in the interpretation of the "ivy-sign" as an MRI pattern. Knowledge of the "ivy-sign" can be helpful, especially in diseases predisposing to MMD. If this MRI pattern is present, MMD should be considered and MR angiography should be added.
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http://dx.doi.org/10.1055/s-0040-1708546DOI Listing
August 2020

Axenfeld-Rieger Anomaly and Neuropsychiatric Problems-More than Meets the Eye.

Neuropediatrics 2020 06 11;51(3):192-197. Epub 2020 Feb 11.

Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Objective: The main purpose of this article is to demonstrate the co-occurrence of Axenfeld-Rieger anomaly and neuropsychiatric problems as clinical signs of genetically determined cerebral small vessel disease in two patients.

Case Study: We report on two adolescent individuals with ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) presenting with neuropsychiatric symptoms. Both patients underwent cerebral magnetic resonance imaging showing white matter T2-hyperintensities involving different brain regions, suspective of cerebral small vessel disease. Genetic analysis revealed pathogenic mutations in the gene (patient 1) and the gene (patient 2), respectively.

Conclusion: We report on the co-occurrence of ocular anterior segment dysgenesis (Axenfeld-Rieger anomaly) and neuropsychiatric symptoms as clinical signs of genetically determined cerebral small vessel disease in two patients. In both patients, the cerebral lesions involved the frontotemporal regions, brain regions that control social behavior as well as executive and cognitive function, highlighting the fact that neuropsychiatric symptoms may be early clinical presentations of cerebral small vessel disease. We further provide a review of monogenic causes of pediatric cerebral small vessel disease, emphasizing the links to childhood-onset neuropsychiatric disease.
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http://dx.doi.org/10.1055/s-0039-3402037DOI Listing
June 2020

Defining and expanding the phenotype of -associated developmental epileptic encephalopathy.

Neurol Genet 2019 Dec 10;5(6):e373. Epub 2019 Dec 10.

Department of Epilepsy Genetics and Precision Medicine (K.J.M., E.G., G.R., R.S.M.), The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.J.M., E.G., R.S.M.), University of Southern Denmark, Odense; Institute of Human Genetics (D.M., R. Jamra, A.F., J.R.L.), University of Leipzig Medical Center, Germany; Institute of Structural Biology (R. Janowski, D.N.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Paediatric Radiology (C.R.), University of Leipzig Medical Center, Germany; Department of Epilepsy, Sleep and Pediatric Neurophysiology (J.T.), Lyon University Hospital, France; Neuropediatric Unit (A.-L.P., D.M.V., G.L.), Lyon University Hospital, France; Department of Medical Genetics (N.C., G.L.), Lyon University Hospital, France; GenDev Team (N.C.), CNRS UMR 5292, INSERM U1028, CNRL and University of Lyon, France; Department of Genetics (E.B.), University Medical Center Utrecht, The Netherlands; Department of Child Neurology (K.G.), Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; Department of Paediatrics (A.P.B.), Copenhagen University Hospital Rigshospitalet, Denmark; Baylor College of Medicine (S.M., K.N.), Children's Hospital of San Antonio; Undiagnosed Diseases Program (G.B., C.P.), Genetic Services of Western Australia, Department of Health, Government of Western Australia, Perth; Western Australian Register of Developmental Anomalies (G.B., D.G.), Australia; Telethon Kids Institute and the School of Paediatrics and Child Health (G.B.), University of Western Australia, Perth; Linear Clinical Research (L.D.), WA, Australia; Center of Human Genetics (S.S), Jena University Hospital, Germany; Department of Neuropediatrics (A.D.), Jena University Hospital, Germany; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Division of Neuropediatrics (A.M.), University of Leipzig Medical Center, Germany; Amplexa Genetics (H.H.), Odense, Denmark; Clinic for Children (H.H.), Værløse, Denmark; Center for Integrative Brain Research (G.M.), Seattle Children's Research Institute, WA; Department of Pediatrics (G.M.), University of Washington, Seattle; Medical Genetics Unit (F.B.), Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Istituto Dermopatico dell'Immacolata (F.B.), IDI-IRCCS, Rome, Italy; Institute of Human Genetics (T.B., M.H.), University Medical Center Hamburg-Eppendorf, Germany; Childrens Hospital (J.D.), University Medical Center Hamburg-Eppendorf, Germany; University of Copenhagen (G.R.), Denmark; Institute for Human Genetics (P.M.), University Hospital Magdeburg, Germany; Children's Hospital A. Meyer (R.G., A.V.), University of Florence, Italy; and Institute of Pharmaceutical Biotechnology (D.N.), Ulm University, Germany.

Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in encephalopathy.

Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.

Results: Biallelic pathogenic variants in cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.

Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new variants and well-founded genetic counseling.
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http://dx.doi.org/10.1212/NXG.0000000000000373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927360PMC
December 2019

Harlequin Syndrome after Thoracoscopic Repair of a Child with Tracheoesophageal Fistula (TEF).

European J Pediatr Surg Rep 2019 Jan 26;7(1):e63-e65. Epub 2019 Sep 26.

Klinik und Poliklinik für Kinderchirurgie, Universitätsklinikum Leipzig, Leipzig, Sachsen, Germany.

Harlequin syndrome (HS) is a rare dysautonomia of the sympathetic nervous system leading to asymmetric facial flushing and sweating. In the literature, only a few cases of HS after thoracoscopic tracheoesophageal fistula (TEF) repair are reported. We report on a newborn with TEF who developed HS after thoracoscopic repair. On the first day of life, the girl (3,480 g, gestation age: 41 week) underwent thoracoscopic repair of a type C esophageal atresia (TEF; OR time 105 minute) without complications. The postoperative course was uneventful, the patient swallowed and thrived well and did not require esophageal dilatations. At 2 years of age, missing facial flushing, transpiration, and warming on the right side of her face during agitation were noticed. As no further intervention was required, the girl and her parents adapted well to the symptoms. Our report shows that the late onset of HS after the surgical procedure is unlikely a direct causal relation to the thoracoscopic operation but rather a shared embryological pathogenesis, like a neurocristopathy.
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http://dx.doi.org/10.1055/s-0039-1697667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763501PMC
January 2019

Recurrent Myalgia since Early Infancy-Misleading Clinical Course in a Child with Carnitine Palmitoyltransferase-II Deficiency.

Neuropediatrics 2020 02 21;51(1):53-56. Epub 2019 Sep 21.

Department for Women and Child Health, Hospital for Children and Adolescents, University Hospitals, University of Leipzig, Leipzig, Germany.

Metabolic myopathies are heterogeneous hereditary diseases affecting skeletal muscle energy supply. Symptoms usually comprise pain, cramps, hypotonia, weakness, and myoglobinuria.We present a boy with recurrent myalgia and weakness after some minutes of exercise or during febrile infections since early infancy. First laboratory workup at the age of 9 years showed no abnormalities, apart from a slightly elevated creatine kinase. After exclusion of common structural and metabolic myopathies, next generation sequencing panel (4 years after the initial diagnostic metabolic workup) revealed two potentially pathogenic missense mutations in the gene (c.149C > A (p.P50H) and c.1459G > A (p.E487K)).Our case underscores the clinical variability of muscle carnitine palmitoyltransferase II (CPT II) deficiency and illustrates a pitfall of diagnostic algorithms for metabolic myopathies. Myalgia following exercise of a few minutes duration would have argued for a carbohydrate and against a fatty acid metabolic defect. However, CPT II deficiency is the most common disorder of muscle fatty acid metabolism and should be considered even in atypical scenarios. Analyses of plasma acyl carnitine profile during acute metabolic crises may help to unmask biochemical markers which are often overlooked in dried-blood analyses.
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http://dx.doi.org/10.1055/s-0039-1694977DOI Listing
February 2020

Childhood Dystonia-Parkinsonism Following Infantile Spasms-Clinical Clue to Diagnosis in Early Beta-Propeller Protein-Associated Neurodegeneration.

Neuropediatrics 2020 02 10;51(1):22-29. Epub 2019 Sep 10.

Department of Pediatric Neurology, Leipzig University Hospital for Children and Adolescents, Leipzig, Sachsen, Germany.

Introduction: Beta-propeller protein-associated neurodegeneration (BPAN) is a very rare, X-linked dominant (XLD) inherited member of the neurodegeneration with brain iron accumulation (NBIA) disease family.

Case Report: We present a female case of BPAN with infantile spasms in the first year, Rett-like symptomatology, focal epilepsy, and loss of motor skills in childhood. Menarche occurred at the age of 9, after precocious pubarche and puberty.Dystonia-parkinsonism as extrapyramidal sign at the age of 10 years resulted in radiological and genetic work-up.

Results: Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) measured 66/120 points in body part-related dystonia symptoms. Cerebrospinal fluid examination showed dopamine depletion.T2 and B0 sequences of the diffusion-weighted magnetic resonance imaging showed susceptibility artifacts with NBIA-typical hypointense globus pallidus (GP) and substantia nigra (SN). Next-generation sequencing revealed a BPAN-causing pathogenic variant in gene (c.830 + 1G > A, XLD, heterozygous, de novo). Skewed X-inactivation was measured (2:98).

Conclusions: Autophagy-related X-linked BPAN disease might still be underdiagnosed in female cases of infantile spasms.Skewed X-inactivation will have mainly influenced the uncommon, very early childhood neurodegenerative symptomatology in the present BPAN case. Oral levodopa substitution led to improvement in sleep disorder, hypersalivation, and swallowing.Reduced white matter and hypointense signals in SN and GP on susceptibility sequences in magnetic resonance imaging are characteristic radiological findings of advanced disease in NBIA. No BPAN-typical halo sign in T1-weighted scan at midbrain level was seen at the age of 11 years. NBIA panel is recommended for early diagnosis.
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http://dx.doi.org/10.1055/s-0039-1696688DOI Listing
February 2020

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - a multicenter retrospective study.

Orphanet J Rare Dis 2019 05 3;14(1):96. Epub 2019 May 3.

Division of Child Neurology and Metabolic Medicine, Center for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Background: Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years.

Results: A total of 17 children (median age at study inclusion 2.4 years, range 0-6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0-19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1-2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3-4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction.

Conclusion: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.
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http://dx.doi.org/10.1186/s13023-019-1077-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500021PMC
May 2019

Epilepsy: a cross-sectional study of paediatricians and general practitioners on their experiences, knowledge and handling of the disease.

Epileptic Disord 2019 Apr;21(2):197-205

University Hospital for Children and Adolescents, Centre for Paediatric Research, Leipzig, University Hospital for Children and Adolescents, Neuropaediatrics, Rostock, Germany.

Epilepsy is a life-changing disease, and patients with epilepsy may face a number of issues. Paediatricians and general practitioners are often the first to be asked for advice. This cross-sectional study was performed to gain information on the knowledge and experiences of paediatricians and general practitioners on epilepsy. From September 2015 to July 2017, paediatricians and general practitioners in Leipzig, Germany, were asked to take part in a face-to-face interview. Overall, 40 paediatricians and 60 general practitioners participated in the study. A total of 99/100 (99%) kept emergency medication available and 96/100 (96%) would administer it during a seizure. Also, 40/40 (100%) of the paediatricians and 34/60 (57%) of the general practitioners recommended that non-professionals should administer emergency medication, and 18/40 (45%) of the paediatricians and 35/60 (58%) of the general practitioners would put an object in the patient's mouth during a seizure. With regards to safety precautions, paediatricians mentioned the risks associated with swimming (30/40; 75%) and the potential of falling from a height (23/40; 58%), whereas general practitioners focused on being around vehicles including driving regulations (43/60; 72%). Only 5/60 (8%) of the general practitioners advised that precautions should be taken during swimming. Fatigue/exhaustion was the most common adverse drug event associated with long-term anticonvulsive therapy mentioned by paediatricians (13/40; 33%) and general practitioners (27/60; 45%). Of all the participants, 23/100 (23%) recommended epilepsy training programmes for patients and families, however, none were able to name a specific programme. Nearly half of the general practitioners did not recommend the use of rescue medication by non-professionals. This measure, however, can prevent the occurrence of prolonged non-treatable seizures. Both paediatricians and general practitioners should bear in mind that placing an object in the mouth during a seizure should be avoided due to the risk of additional injury. To reduce the risk of drowning, physicians should recommend safety precautions during swimming. Information on epilepsy training programmes for patients and families should be diffused to all physicians taking care of patients with epilepsy.
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http://dx.doi.org/10.1684/epd.2019.1048DOI Listing
April 2019

Neurologic phenotypes associated with / mutations: Expanding the spectrum of disease.

Neurology 2018 11 9;91(22):e2078-e2088. Epub 2018 Nov 9.

From the Department of Clinical and Experimental Epilepsy (S.Z., Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.) and Division of Neuropathology (Z.M., M.T.), UCL Institute of Neurology, London, UK; Clinic of Neurology (S.Z.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy; Department of Pediatric Neurology and Neurological Rehabilitation (C.S., T.H., P.W., G.J.K.) and Neurosurgery Clinic and Clinic for Epilepsy Surgery (M.K.), Schön Klinik Vogtareuth; Department of Pediatrics (C.S., M.S.), Children's Hospital Augsburg, Germany; UCL Great Ormond Street Institute of Child Health (J.R.N., K.V., S.M.V., J.H.C.), London, UK; Paediatric Neurology and Neurogenetics Unit and Laboratories (D.M., R.G.), A. Meyer Children's Hospital, University of Florence, Italy; Chalfont Centre for Epilepsy (Z.M., L.H.-H., S.K., S. Balestrini, S.M.S.), Chalfont-St-Peter, Buckinghamshire, UK; CeGaT-Center for Genomics and Transcriptomics (A.P., S. Biskup), Tübingen, Germany; Neurogenetics Unit (M.L.), Department of Medical Genetics, Hospital de São João, Porto, Portugal; Department of Pediatrics and Adolescent Medicine (J.G.), University Medical Center Göttingen; Hospital for Children and Adolescents (A.M.), University Clinic Leipzig, Germany; Freiburg Medical Laboratory (M.J.), Dubai; The Danish Epilepsy Centre (R.S.M., E.G.), Dianalund; Institute for Regional Health Services (R.S.M., E.G.), University of Southern Denmark, Odense; Department of Clinical Genetics (B.S.K.), Odense University Hospital; Hans Christian Andersen Children's Hospital (L.K.H.), Odense, Denmark; Pediatric Neurology and Muscular Diseases Unit (M.S.V., P.S.), Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa "G. Gaslini" Institute, Italy; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Department of Neurology (S.D., C.L.S.-H.), Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD; Center for Genomic Medicine (N.H.-F.), Tohoku University; Department of Pediatrics (N.H.-F.), Tohoku University School of Medicine, Sendai, Japan; Department of Pediatrics (T.T., R.L.) and Institute of Clinical Medicine (K.O.), University of Tartu; Children's Clinic (T.T., R.L.), Department of Radiology (P.I.), and Department of Clinical Genetics, United Laboratories (K.O.), Tartu University Hospital, Estonia; Ludwig-Maximilians-University Munich (I.K.); Department of Pediatric Neurology (A.H.), Clinic Traunstein; Children's Hospital (M.K.), Dr. Horst Schmidt Klinik, Wiesbaden; Altona Children's Hospital (J.H.), Hamburg; Department of Pediatrics (C. Makowski), Technische Universität München, Germany; Department of Clinical Genetics (S.G.), Royal North Shore Hospital, St Leonards; John Hunter Children's Hospital (G.M.S.), New Lambton Heights, New South Wales, Australia; Department of Neurology (R.T.), University Hospital of Wales; Institute of Psychological Medicine and Clinical Neurosciences (R.H.T.), Cardiff University; Division of Neuroradiology (C. Micallef), National Hospital for Neurology and Neurosurgery, London; Department of Brain Repair & Rehabilitation (D.J.W.), Stroke Research Centre, UCL Institute of Neurology, London, UK; Paracelsus Medical University (G.J.K.), Salzburg, Austria; and IRCCS Stella Maris Foundation (R.G.), Pisa, Italy.

Objective: To characterize the neurologic phenotypes associated with mutations and to seek genotype-phenotype correlation.

Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with mutations.

Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across and a clear genotype-phenotype correlation did not emerge.

Conclusion: mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.
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http://dx.doi.org/10.1212/WNL.0000000000006567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282239PMC
November 2018

Experiences, expectations, and fears of adolescents with epilepsy or bronchial asthma.

Eur J Pediatr 2018 Oct 3;177(10):1451-1457. Epub 2018 Jul 3.

University Hospital for Children and Adolescents, Centre of Pediatric Research, Liebigstraße 20a, 04103, Leipzig, Germany.

Epilepsy and bronchial asthma are frequent in adolescents. Data on adolescents' experiences with their disease and on their expectations for the future, however, is scarce. Patients of a university hospital aged 12 to 17 with epilepsy or bronchial asthma were interviewed based on a questionnaire. Forty-five patients with epilepsy and 47 with bronchial asthma were interviewed. Adolescents with epilepsy felt more impaired by their disease (median 2.5; Q25/Q75 0.75/3.0; 6-level Likert scales: 0 = not at all, 5 = very strong) than those with asthma (1.0; 0/3.0; p = 0.017). Seventy-nine patients (85.9%) had never used the Internet to gain information about their disease. Adolescents with epilepsy felt more limited in their career possibilities by their disease (2.0; 0/4.0) than those with asthma (0; 0/2.0; p = 0.001) and had a higher level of concern about passing their disease on to their children (3.0; 0/4.0) than their peers with asthma (1.5; 1.5/3.0; p = 0.016). Girls with epilepsy were more anxious (4.0; 0.5/5.0) than girls with asthma (0; 0/4.0) about complications of the disease regarding pregnancy (p = 0.019).

Conclusion: As well adolescents with epilepsy as with asthma described limitations of their daily life and concerns about the future. What is Known: • Epilepsy and bronchial asthma are frequent chronic diseases in adolescents. • Those diseases can affect psychosocial development. What is New: • Adolescents with epilepsy and bronchial asthma described a high burden of their disease, and most adolescents had not used the Internet to inform themselves on their disease. • Especially adolescents with epilepsy fear limitations in their job possibilities, inheritance of their disease and complications in their prospective pregnancy.
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http://dx.doi.org/10.1007/s00431-018-3200-4DOI Listing
October 2018

Optimizing parents' performance in anticonvulsant rescue medication administration.

Epilepsy Behav 2018 07 7;84:37-43. Epub 2018 May 7.

Drug Safety Center and Dept. of Clinical Pharmacy, Leipzig University, Brüderstraße 32, 04103 Leipzig, Germany. Electronic address:

Objective: Parents of children with epilepsy are at risk of committing high-risk handling errors with a high potential to harm the patient when administering anticonvulsant rescue medication. We developed a training concept addressing identified high-risk handling errors and investigated its effects on parents' skills.

Study Design: In a controlled prospective intervention study, parents of children with epilepsy were asked to demonstrate their administration of rescue medication by using dummy dolls. A clinical pharmacist monitored rectal or buccal administration and addressed errors in the intervention group with training and information sheets. Three to 6weeks later, intervention's sustainability was assessed at a home visit.

Results: One hundred sixty-one parents completed full study assessment: 92 in the intervention group and 69 in the control group. The number of processes with at least one handling error was reduced from 96.4% to 56.7% in rectal tube administration and from 66.7% to 13.5% in buccal administration (both p<0.001).

Conclusion: A one-time intervention for parents significantly and sustainably reduced high-risk handling errors. Dummy dolls and information sheet were adequate for an effective and feasible training to support the correct administration of anticonvulsant rescue medication.
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http://dx.doi.org/10.1016/j.yebeh.2018.02.032DOI Listing
July 2018

Do we need gadolinium-based contrast medium for brain magnetic resonance imaging in children?

Pediatr Radiol 2018 06 6;48(6):858-864. Epub 2018 Apr 6.

Department of Paediatric Radiology, University Leipzig, Liebigstrasse 20a, 04103, Leipzig, Germany.

Background: Brain imaging is the most common examination in pediatric magnetic resonance imaging (MRI), often combined with the use of a gadolinium-based contrast medium. The application of gadolinium-based contrast medium poses some risk. There is limited evidence of the benefits of contrast medium in pediatric brain imaging.

Objective: To assess the diagnostic gain of contrast-enhanced sequences in brain MRI when the unenhanced sequences are normal.

Materials And Methods: We retrospectively assessed 6,683 brain MR examinations using contrast medium in children younger than 16 years in the pediatric radiology department of the University Hospital Leipzig to determine whether contrast-enhanced sequences delivered additional, clinically relevant information to pre-contrast sequences. All examinations were executed using a 1.5-T or a 3-T system.

Results: In 8 of 3,003 (95% confidence interval 0.12-0.52%) unenhanced normal brain examinations, a relevant additional finding was detected when contrast medium was administered. Contrast enhancement led to a change in diagnosis in only one of these cases.

Conclusion: Children with a normal pre-contrast brain MRI rarely benefit from contrast medium application. Comparing these results to the risks and disadvantages of a routine gadolinium application, there is substantiated numerical evidence for avoiding routine administration of gadolinium in a pre-contrast normal MRI examination.
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http://dx.doi.org/10.1007/s00247-017-3999-2DOI Listing
June 2018

Pre-anesthetic assessment with three core questions for the detection of obstructive sleep apnea in childhood: An observational study.

BMC Anesthesiol 2018 02 20;18(1):25. Epub 2018 Feb 20.

Department of Neuropediatric, University Hospital Leipzig, Liebigstr. 20, 04103, Leipzig, Germany.

Background: Children with obstructive sleep apnea are at high risk for perioperative airway obstruction. Many "at risk" children may remain unrecognized. The aim of this study is to find a clinically practicable test to identify obstructive sleep apnea in childhood.

Methods: In this pilot study, we prospectively compared four parental questionnaires with the respective findings of subsequent sleep laboratory testing in children. Right before sleep laboratory testing, children's parents answered both the Pediatric Sleep Questionnaire, a subscale of the Sleep Related Breathing Disorder questionnaire (PSQ-SRBD-Subscale), and an eight-item questionnaire derived from it. Finally, we condensed the eight-item questionnaire to three core issues: Does your child regularly snore at night? Does your child demonstrate labored breathing during sleep? Does your child have breathing pauses during sleep? With it, two similar questionnaires were generated that differed in the formation of the resulting score. One questionnaire was built by a quotient comparable to the abovementioned questionnaires and a second as quick test that functioned as a simple sum score. Both sensitivity and specificity were determined by using a Receiver Operating Characteristic analysis.

Results: In total, 53 children were included in the study. Both the PSQ-SRBD-questionnaire and self-derived eight-item questionnaire failed to reach statistically significant results in detecting obstructive sleep apnea. The set of three core questions with a score built by a quotient was statistically significant and provided sensitivity and a moderate specificity of 0.944 and 0.543, respectively. This could be slightly optimized by creating a simple sum-score (specificity of 0.571).

Conclusions: The use of three core-questions may facilitate the detection of pediatric obstructive sleep apnea within the scope of the anesthesia survey. While the study has some limitations, future studies with both unselective collectives and older children might prove this ultra-short questionnaire to be advantageous in detecting pediatric OSA in clinical practices.

Trial Registration: German Clinical Trial Register ( DRKS00010408 , https://www.drks.de ); date of registration 26.07.2016.
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http://dx.doi.org/10.1186/s12871-018-0483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819204PMC
February 2018

MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein.

J Neurol 2018 Apr 8;265(4):845-855. Epub 2018 Feb 8.

Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.

Antibodies against the myelin oligodendrocyte glycoprotein (MOG-Ab) can be detected in various pediatric acquired demyelinating syndromes (ADS). Here, we analyze the spectrum of neuroradiologic findings in children with MOG-Ab and a first demyelinating event. The cerebral and spinal MRI of 69 children with different ADS was assessed in regard to the distribution and characteristics of lesions. Children with acute disseminated encephalomyelitis (n = 36) or neuromyelitis optica spectrum disorder (n = 5) presented an imaging pattern characterized predominantly by poorly demarcated lesions with a wide supra- and infratentorial distribution. Younger children also tended to have poorly defined and widespread lesions. The majority of patients with an isolated optic neuritis (n = 16) only presented small non-specific brain lesions or none at all. A longitudinally extensive transverse myelitis mainly affecting the cervical, and less often so the thoracic, lumbar, and conus regions, was detected in 31 children. The three children of our cohort who were then finally diagnosed with multiple sclerosis had at onset already demarcated white matter lesions as well as transverse myelitis. In conclusion, children with MOG seropositive ADS present disparate, yet characteristic imaging patterns. These patterns have been seen to correlate to the disease entity as well as to age of symptom onset.
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http://dx.doi.org/10.1007/s00415-018-8781-3DOI Listing
April 2018

[Interdisciplinary Concepts of Paediatrics and Clinical Pharmacy to Optimise Anticonvulsant Treatment].

Klin Padiatr 2018 01 19;230(1):5-12. Epub 2017 Dec 19.

Klinik und Poliklinik für Kinder und Jugendliche, Zentrum für pädiatrische Forschung, Universitätsklinikum Leipzig.

Expertise in a variety of fields is required for the diagnostic process of epilepsies in children and adolescents as well as for their treatment with anticonvulsants. Patients benefit in the process from the cooperation of different health care professionals. It is of critical importance for risks to be minimised and for the efficacy shown in controlled clinical trials to be maintained in routine conditions. In the first instance, drug prescription procedures, including the choice of anticonvulsants and combinations of drugs and dosing, have to be considered. The administration of drugs has, of course, also to be taken into account. Only if patients are given their anticonvulsants appropriately, the intended success of the therapy can be accomplished. Strategies aimed at improving drug administration have to be directed not only at nurses but also at parents, children and adolescents themselves, as well as caregivers in schools and children's day-care facilities. By providing theoretical teaching, practical training, and routinely including pharmacists in the therapeutic team, drug-related problems that may result in limited effectiveness and increased risks are prevented. As a result, drug (therapy) safety is not only qualitatively improved, but the degree of participation and quality of life of patients and families is improved as well.
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http://dx.doi.org/10.1055/s-0043-120525DOI Listing
January 2018

How do Parents Perceive the Initial Medical Consultation on their Child's Developmental Disorder?

Klin Padiatr 2018 01 19;230(1):44-49. Epub 2017 Dec 19.

Klinik und Poliklinik für Kinder und Jugendliche, Zentrum für pädiatrische Forschung, Universitätsklinikum Leipzig.

Background: A developmental disorder of a child has a major impact on the affected families' lives. However, data about the parents' perception of the revealing of the diagnosis is scarce.

Patients And Methods: Parents of children with developmental disorder treated as outpatients in a university hospital were interviewed about the initial medical consultation concerning the diagnosis of their child.

Results: Parents of 210 children agreed to take part in the study. 35/210 (17%) had to be excluded from the study as they were not able to remember the initial medical consultation, or claimed there was either no initial medical consultation or they did not attend it. The diagnosis of developmental disorder was made in median 4 months (Q25/Q75: 0/12; min/max: 0/63) after the parents had noticed the first symptoms. According to the parents, options to support the development of the child were the most frequently addressed topic in the initial medical consultation (119/175, 68%). Some parents wished more empathy (19/175, 11%), and less medical terminology (12/175, 7%). 114/175 (65%) of parents rated the initial medical consultation as "very good" or "good". After their initial medical consultation, 66/175 (38%) of the parents had open questions mainly concerning the prognosis of the disease. Sources of information that were used after the consultation were most often the treating physician (150/175, 86%) and the internet (133/175, 76%).

Conclusion: Generally, parents perceive the initial medical consultation on the developmental disorder of their child well. Nevertheless, many parents state that they had unanswered questions after the consultation. The internet is one of the main sources parents use to answer those questions.
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http://dx.doi.org/10.1055/s-0043-117960DOI Listing
January 2018

Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

Brain 2017 Sep;140(9):2322-2336

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department, A Meyer Children's Hospital, University of Florence, Florence, Italy.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.
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http://dx.doi.org/10.1093/brain/awx195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248409PMC
September 2017

[Anti-Myelin Oligodendrocyte Glycoprotein Antibodies in Paediatric Patients with Optic Neuritis].

Klin Monbl Augenheilkd 2017 Oct 12;234(10):1243-1249. Epub 2017 Oct 12.

Neuropädiatrie, Universitätsklinik und Poliklinik für Kinder und Jugendliche Leipzig, Leipzig.

Myelin oligodendrocyte glycoprotein (MOG) is located on the surface of oligodendrocytes and myelin in the central nervous system. MOG-IgG is associated with acute disseminated encephalomyelitis (ADEM), relapsing and bilateral optic neuritis (NNO), and transverse myelitis (TM) in both paediatric and adult patients. The combination of NNO and TM or other inflammatory brain lesions is a typical feature of neuromyelitis optica spectrum disorders (NMO-SD) which are associated with specific pathogenic autoantibodies against the water channel aquaporin-4 (AQP4-IgG). However, children with NMO-SD are often seronegative for AQP4-IgG but seropositive for MOG-IgG. Therefore, the course and therapy of MOG-IgG positive NNO in children were of special interest. The course of disease of two male patients with acute NNO is presented (bilateral NNO, age of onset 8 years each, AQP4-IgG negative, MOG-IgG positive). Several relapses of NNO occurred in patient 1 with persisting MOG-IgG in spite of immunsuppressive therapy. He suffered from increasing optic atrophy, considerable visual loss and transient brainstem affection. Patient 2 showed a monophasic course of disease with a rapid decline in MOG-IgG titre and only minor asymmetric optic atrophy. MOG-IgG in children is associated with recurrent NNO and cerebral lesions characteristic of ADEM or NMO-SD. High titres of MOG-IgG are observed during the acute phase of clinical symptoms. Relapses of NNO lead to increasing loss of retinal nerve fibre layer. Diagnostic investigation includes the determination of AQP4-IgG and MOG-IgG as well as magnetic resonance imaging (MRI) of brain and spinal cord. The therapeutic consequence of this is consistent immunsuppressive treatment, starting with intravenous steroids and followed by second-line therapy with steroid sparing immunosuppressants, including mycophenolate or azathioprine, followed in refractory cases by rituximab. The therapeutic effect should be controlled by laboratory tests of MOG-IgG titre.
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http://dx.doi.org/10.1055/s-0043-120067DOI Listing
October 2017

[Acute Bilateral Abducens Nerve Palsy in a 7-Year-Old Boy - Atypical Miller Fisher Syndrome].

Klin Monbl Augenheilkd 2017 10 12;234(10):1225-1227. Epub 2017 Oct 12.

Neuropädiatrie, Universitätsklinik und Poliklinik für Kinder und Jugendliche, Leipzig.

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http://dx.doi.org/10.1055/s-0043-118222DOI Listing
October 2017

Severe gyration and migration disorder in fetofetal transfusion syndrome: two case reports and a review of the literature on the neurological outcome of children with lesions on neuroimaging.

Childs Nerv Syst 2018 01 2;34(1):155-163. Epub 2017 Oct 2.

Division of Neuropediatrics, Hospital for Children and Adolescents, University of Leipzig, Liebigstraße 20a, 04103, Leipzig, Germany.

Introduction: Fetofetal transfusion syndrome is a dreaded cause of morbidity and mortality in monochorionic pregnancies.

Case Reports: We present two pairs of twins one of which we have followed for more than 6 years. The donors suffer from cerebral palsy, orofacial, and motor problems, and both are significantly smaller than their recipient twins. Interestingly, cranial MRI revealed medial frontal lobe polymicrogyria, ventriculomegaly, and decreased thickness in both parietal lobes in both donors. We suggest this as a possible feature of fetofetal transfusion syndrome.

Review: A minireview of the literature on neuroimaging and neurodevelopmental outcome in fetofetal transfusion syndrome is presented.

Conclusion: While the close resemblance of the imaging features of both cases is likely incidental further study of a connection between migration and gyration disorders and fetofetal transfusion syndrome is warranted.
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http://dx.doi.org/10.1007/s00381-017-3595-7DOI Listing
January 2018

Knowledge and attitudes about epilepsy: A survey of high school students in Germany.

Seizure 2017 Oct 24;51:139-144. Epub 2017 Aug 24.

University Hospital for Children and Adolescents, Centre for Paediatric Research, Liebigstr. 20a, 04103 Leipzig, Germany. Electronic address:

Purpose: Attitudes concerning epilepsy improved over the last few decades, but children with epilepsy still suffer from stigmatisation. Data about unaffected children's knowledge of and attitudes about epilepsy is scarce.

Methods: We developed a questionnaire regarding epilepsy for high school students attending 8th-10th grade. The survey was performed from October 2015 to March 2016 in 5 different federal states of Germany.

Results: 1092 students [mean age (Q25/75): 14.5 (14/15) years] participated. 542/1092 (50%) of the respondents knew that people could die from a seizure. 216/1092 (20%) thought emotional strain could cause epilepsy. Asked for measures they would perform in case of a seizure, 235/1092 (24%) participants would hold the person to the ground, and 182/1092 (19%) would put a solid object into the person's mouth. 28/1092 (3%) would not like to be friends with a person with epilepsy, and 237/1092 (22%) would not like to go on a date with a person with epilepsy. Answers of 342/1092 (31%) students of a school located nearby a specialised epilepsy centre differed in some questions. The latter students were more familiar with epilepsy and showed better knowledge concerning causes, symptoms and treatment of epilepsy. In a question about special characteristics of people with epilepsy, 63/342 (18%) [other schools: 52/750 (11%)] answered people with epilepsy were friendlier and 76/342 (22%) [other schools: 49/750 (11%)] answered they were more sociable compared to people without epilepsy.

Conclusion: To improve knowledge and attitudes and reduce misconceptions further education seems necessary.
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http://dx.doi.org/10.1016/j.seizure.2017.08.008DOI Listing
October 2017

Seizure disorders and developmental disorders: impact on life of affected families-a structured interview.

Eur J Pediatr 2017 Aug 9;176(8):1121-1129. Epub 2017 Jul 9.

Center for Pediatric Research, University Hospital for Children and Adolescents, Liebigstraße 20a, 04103, Leipzig, Germany.

Seizure disorder and developmental disorder are two of the most common chronic disorders in childhood. Data on perceived parental burden and specific effects on daily life is scarce. We performed a structured interview, consecutively talking to all parents of pediatric outpatients of our university hospital diagnosed with seizure or developmental disorder. Three hundred seven parents (of 317 affected children: 53 with seizure disorder, 44 with specific developmental disorder, 35 with learning disorder, 71 with intellectual disability, 15 with seizure + specific developmental disorder, 23 with seizure + learning disorder, 76 with seizure disorder + intellectual disability) were interviewed. Parents of children with both seizure disorder and intellectual disability stated the highest constraints in daily life, regarding friends, hobbies, emotional pressure, occupation, partnership, habitation, and financial burden. Due to diagnosis of seizure or developmental disorder, 155/307 (51%) parents reduced their working hours/stopped working, 62/307 (20%) changed their habitation, and 46/307 (15%) broke up. As judged by parents, 148/317 (47%) children are being discriminated against, even own family/friends and educators are held responsible.

Conclusion: Parents perceive changes in their daily life and discrimination of their children due to their children's seizure and developmental disorders. An intellectual disability combined with seizure disorder caused the highest constraint. What is Known: • Seizure and/or developmental disorders of children may adversely influence quality of life for affected parents. • Caring for a child with special health care needs can take complete attention and own parental needs may therefore be difficult to meet. What is New: • Two out of three parents stated changes of their daily life such as quitting work, change of habitation, or breakup of partnership due to their child's diagnosis. • As judged by the parents, one in two children with developmental disorder of any kind is being discriminated against, even teachers and own family are held responsible.
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http://dx.doi.org/10.1007/s00431-017-2958-0DOI Listing
August 2017